a) Field of the Invention
The present invention relates to a series of novel N-substituted imide derivatives and non-toxic salts thereof, which have a high affinity for the serotonin 5-HT.sub.1A receptor, acting as partial agonists and antagonists and are useful for preventing and treating serotonergic neuron-related diseases.
b) Description of the Prior Art
It is known that serotonin [5-hydroxytryptamine (5-HT)] as a neurotransmitter has correlations with various physiological phenomena, such as appetite, memory, thermoregulation, sleep, sexual behavior, anxiety, depression and stress [Glennon, R. A., J. Med. Chem., 30, 1 (1987)].
It is also known that compounds acting on a 5-HT.sub.1A receptor which is one of the serotonin-susceptive receptors are useful for preventing and treating anxiety, depression, eating disorders, high blood pressure and emesis. Results of studies on various compounds have been reported [see "Nippon Rinsho (Japanese Journal of Clinical Medicine)" vol. 47, special edition. pp. 1241-1248 (1989); J. P. Feighnev, W. F. Boyer, Psychopathology, 22, 21 (1989); P. R. Saxena, C. M. Villalon, TIPS, 11, 95 (1990); N. Matsuki, et al., Jpn. J. Pharmacol. Suppl., 58, 313 (1992).
Compounds having selective partial agonist activity at the 5-HT.sub.1A receptor have established a presence in the marketplace as effective anxiolytic agents (buspirone HCl, 8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4. 5]decane-7,9-dione monohydrochloride, U.S. Pat. No. 3,717,634). 5-HT.sub.1A agonists and antagonists are being evaluated in the laboratory and in the clinic for use in the treatment of several diseases such as anxiety, depression, schizophrenia, the cognitive deficits resulting from neurodegenerative diseases like Alzheirner's Disease, and additionally prostate cancer (K. Rasmussen and V. P. Rocco, Recent Progress in Serotonin (5-HT.sub.1A Receptor Modulators, in Annual Reports in Medicinal Chemistry, Volume 30, J. A. Bristol, ed., pp. 1-9 (1995)).
A series of naphylpiperazines useful as 5-HT.sub.1A receptor ligands having the generic structure: ##STR2##
are described in EPO 434561-A2 and U.S. Pat. Nos. 5,143,916; 5,162,321; 5,162,324; 5,166,156 and 5,166,157.
Reported in WO 9640136-A1 is a series of N-(piperidinyl or piperazinyl alkyl)phenyl acetamide derivatives as alpha 1a adrenergic receptor antagonists having the generic formula: ##STR3##
EP 795328-A1 discloses a new use for naphthalene serotonin 5-HT.sub.1D receptor antagonists of the generic formula: ##STR4##
as inhibitors of cell growth in human small cell lung carcinoma, where R.sub.1 is a moiety of formulae: ##STR5##
Reported in GB 2303303-A is a method of using 5HT.sub.1A or 5HT.sub.2 receptor antagonists of the formulae: ##STR6##
for preventing or reducing the side effects of serotonin re-uptake inhibitors PA1 n is an integer of 0 to 5; PA1 X is a moiety selected from the group consisting of: ##STR8## PA1 Y is a moiety selected from the group consisting of: ##STR9## PA1 R.sub.2 is independently H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, hydroxy, --(CH.sub.2).sub.z --O-alkyl of 1 to 6 carbon atoms, --(CH.sub.2).sub.z --S-alkyl of 1 to 6 carbon atoms, --(CH.sub.2).sub.z OH, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, --CN, --NO.sub.2, and halogen; aryl of 6 to 12 carbon atoms optionally substituted with one or more substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, --CN, --NO.sub.2, and halogen; heteroaryl having 5 or 6 ring atoms containing 1 to 3 heteroatoms which may be the same or different, selected from nitrogen, oxygen and sulfur, optionally substituted with 1 to 3 substituents which may be the same or different selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, --CN, --NO.sub.2, and halogen; bicyclic heteroaryl having 8 to 20 ring atoms containing 1 to 3 heteroatoms which may be the same or different selected from nitrogen, oxygen and sulfur optionally substituted with 1 to 3 substituents which may be the same or different, selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, --CN, --NO.sub.2, and halogen; PA1 z is an integer of 1 to 3; PA1 R.sub.3 is independently cycloalkyl or cycloalkenyl of 3 to 10 carbon atoms; PA1 R.sub.4 is aryl of 6 to 12 carbon atoms optionally substituted with one or more substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, --CN, --NO.sub.2, and halogen; having 5 or 6 ring atoms containing 1 to 3 heteroatoms which may be the same or different, selected from nitrogen, oxygen and sulfur, optionally substituted with 1 to 3 substituents which may be the same or different selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, --CN, --NO.sub.2, and halogen; bicyclic heteroaryl having 8 to 20 ring atoms containing 1 to 3 heteroatoms which may be the same or different selected from nitrogen, oxygen and sulfur optionally substituted with 1 to 3 substituents which may be the same or different, selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, --CN, --NO.sub.2, and halogen; PA1 with the proviso that X is not the radical ##STR10## PA1 a) compounds having the general formula: ##STR12## PA1 R.sub.2, R.sub.3, X and n are hereinbefore defined; PA1 b) compounds having the general formula: ##STR13## PA1 R.sub.2, R.sub.4, X and n are hereinbefore defined; PA1 c) compounds having the general formula: ##STR14## PA1 R.sub.2, R.sub.3, R.sub.4, X and n are hereinbefore defined; PA1 d) compounds of the general Formula (I) PA1 R.sub.1 is selected from phenyl optionally substituted with 1 or 2 substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, --CN, --NO.sub.2, and halogen; 2 or 3-furyl, 2 or 3-thienyl, 2-,3- or 4-pyridyl, indolyl, azaindolyl, benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl, benzodioxanyl, benzopyranyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, benzothiazolyl, benzothiadiazolyl, benzooxazolyl and 2,3-dihydro-benzo[1,4]dioxin; and R.sub.2, R.sub.3, R.sub.4, X and n are hereinbefore defined; PA1 e) compounds of the general Formula (I) PA1 R.sub.2 is selected from H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, hydroxy, --(CH.sub.2).sub.z --O-alkyl of 1 to 6 carbon atoms, --(CH.sub.2).sub.z --S-alkyl of 1 to 6 carbon atoms, --(CH.sub.2).sub.z OH, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, --CN, --NO.sub.2, and halogen; phenyl optionally substituted with 1 or 2 substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 1 to 6 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, and perhaloalkoxy of 1 to 10 carbon atoms, --CN, --NO.sub.2, and halogen; 2 or 3-furyl, 2 or 3-thienyl, 2-,3- or 4-pyridyl, indolyl, azaindolyl, benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl, benzodioxanyl, benzopyranyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, benzothiazolyl, benzothiadiazolyl, benzooxazolyl and 2,3-dihydro-benzo[1,4]dioxin; and R.sub.1, R.sub.3, R.sub.4, Y, X, z and n are hereinbefore defined. PA1 a) compounds having the general formula: ##STR15## PA1 R.sub.1, R.sub.2, R.sub.3, and n are hereinbefore defined; PA1 b) compounds having the general formula: ##STR16## PA1 R.sub.1, R.sub.2, R.sub.4 and n are hereinbefore defined; PA1 c) compounds having the general formula: ##STR17## PA1 R.sub.1, R.sub.2, R.sub.3, R.sub.4, and n are hereinbefore defined; PA1 d) compounds having the general formula: ##STR18## PA1 R.sub.1 is phenyl optionally substituted with one or two substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, --CN, --NO.sub.2, and halogen; indolyl and 2,3-dihydro-benzo[1,4]dioxin; and R.sub.2 and n are hereinbefore defined; PA1 e) compounds having the general formula: ##STR19## PA1 R.sub.1 is phenyl optionally substituted with one or two substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, --CN, --NO.sub.2, and halogen; indolyl and 2,3-dihydro-benzo[1,4]dioxin; PA1 R.sub.4 is phenyl, optionally substituted with one, two or three substituents selected from alkyl of 1 to 6 carbon atoms, cycloallyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, --CN, --NO.sub.2, and halogen; and PA1 R.sub.2 and n are hereinbefore defined; PA1 f) compounds having the general formula: ##STR20## PA1 R.sub.1 is phenyl optionally substituted with one or two substituents selected alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, --CN, --NO.sub.2, and halogen; indolyl and 2,3-dihydro-benzo[1,4]dioxin; PA1 R.sub.4 is phenyl, optionally substituted with one, two or three substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, --CN, --NO.sub.2, and halogen; and PA1 R.sub.2 and n are hereinbefore defined.
Reported in DE 19520499-A1, WO 9608480A1, and U.S. Pat. Nos. 5,696,123 and 5,708,006 is a series of aralkyl amines, amides and ureas as neurokinin antagonists.
The N-substituted imide derivatives or pharmaceutically acceptable salts thereof of the present invention and described herein are useful in the treatment of disorders associated with serotonergic neuron-related diseases such as anxiety, depression, eating disorders, high blood pressure, emesis, schizophrenia, the cognitive deficits resulting from neurodegenerative diseases of Alzheimer's Disease and additionally prostate cancer.